Amino acid derivatives cyclized at the C-terminal

ABSTRACT

Novel α-substituted Trp dipeptoid derivatives cyclized at the C-terminal useful as agents in the treatment of obesity, hypersecretion of gastric acid in the gut, gastrin-dependent tumors, or as antipsychotics are disclosed. Further, the compounds are antianxiety agents and antiulcer agents. They are agents useful for preventing the response to the withdrawal from chronic treatment with or use of nicotine, diazepam, alcohol, cocaine, caffeine, or opioids. The compounds of the invention are also useful in treating and/or preventing panic attacks. Also disclosed are pharmaceutical compositions and methods of treatment using the compounds as well as processes for preparing them and novel intermediates useful in their preparation. An additional feature of the invention is the use of the compounds in diagnostic compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional application of U.S. Ser. No. 08/049,721 filed Apr.20, 1993, now U.S. Pat. No. 5,397,788; which is a continuation-in-partapplication of U.S. Ser. No. 07/726,654, filed Jul. 12, 1991, now U.S.Pat. No. 5,244,915, issued Sep. 14, 1993; which is acontinuation-in-part application of U.S. Ser. No. 07/576,296, filed Aug.31, 1990, now abandoned.

BACKGROUND OF THE INVENTION

Agents acting at central cholecystokinin (CCK) receptors may inducesatiety (Schick, Yaksh and Go, Regulatory Peptides 14:277-291, 1986).They are also expected to act as analgesics (Hill, Hughes and Pittaway,Neuropharmacology 26:289-300, 1987), and as anticonvulsants (MacVicar,Kerrin and Davison, Brain Research 406:130-135, 1987).

Reduced levels of CCK-peptides have been found in the brains ofschizophrenic patients compared with controls (Roberts, Ferrier, Lee,Crow, Johnstone, Owens, Bacarese-Hamilton, McGregor, O'Shaughnessey,Polak and Bloom. Brain Research 288:199-211, 1983). It has been proposedthat changes in the activity of CCK neurones projecting to the nucleusaccumbens may play a role in schizophrenic processes by influencingdopaminergic function (Totterdell and Smith, Neuroscience 19:181-192,1986). This is consistent with numerous reports that CCK peptidesmodulate dopaminergic function in the basal ganglia and particularly thenucleus accumbens (Weiss, Tanzer, and Ettenberg, Pharmacology,Biochemistry and Behaviour 30:309-317, 1988; Schneider, Allpert andIversen, Peptides 4:749-753, 1983). It may therefore be expected thatagents modifying CCK receptor activity may have therapeutic value inconditions associated with disturbed function of central dopaminergicfunction such as schizophrenia and Parkinson's disease.

CCK and gastrin peptides share a common carboxy terminal pentapeptidesequence and CCK peptides can bind to the gastrin receptor of thestomach mucosa and elicit acid secretion in many species including human(Konturek, Gastrointestinal Hormones, Ch. 23, pp 529-564, 1980, ed. G.B. J. Glass, Raven Press, N.Y.). Antagonists of the CCK-B receptor wouldalso be expected to be antagonists at the stomach gastrin receptor andthis would also be of value for conditions involving excessive acidsecretion.

CCK and gastrin peptides have trophic effects on the pancreas andvarious tissues of the gastrointestinal tract (Johnson, ibid., pp507-527), actions which are associated with increased DNA and RNAsynthesis. Moreover, gastrin secreting cells are associated with certaingastrointestinal tumors as in the Zollinger-Ellison syndrome (Stadil,ibid., pp 729-739), and some colorectal tumors may also be gastrin/CCKdependent (Singh, Walker, Townsend and Thompson, Cancer Research46:1612, 1986; and Smith, J. P., Gastroenterology 95:1541, 1988).Antagonists of CCK/gastrin receptors could therefore be of therapeuticvalue as antitumor agents.

The CCK peptides are widely distributed in various organs of the bodyincluding the gastrointestinal tract, endocrine glands, and the nervesof the peripheral and central nervous systems. Various biologicallyactive forms have been identified including a 33-amino acid hormone andvarious carboxyl-terminus fragments of this peptide (e.g., theoctapeptide CCK26-33 and the tetrapeptide CCK30-33). (G. J. Dockray, Br.Med. Bull. 38(3):253-258, 1982).

The various CCK peptides are thought to be involved in the control ofsmooth muscle contractility, exocrine and endocrine gland secretion,sensory nerve transmission, and numerous brain functions. Administrationof the native peptides cause gall bladder contraction, amylasesecretion, excitation of central neurons, inhibition of feeding,anticonvulsive actions and other behavioral effects. ("Cholecystokinin:Isolation, Structure and Functions," G. B. J. Glass, Ed., Raven Press,New York, 1980, pp 169-221; J. E. Morley, Life Sciences 27:355-368,1980; "Cholecystokinin in the Nervous System," J. de Belleroche and G.J. Dockray, Ed., Ellis Horwood, Chichester, England, 1984, pp 110-127.)

The high concentrations of CCK peptides in many brain areas alsoindicate major brain functions for these peptides (G. J. Dockray, Br.Med. Bull. 38(3):253-258, 1982). The most abundant form of brain CCKfound is CCK26-33, although small quantities of CCK30-33 exist (Rehfeldand Gotterman, J. Neurochem, 32:1339-1341, 1979). The role of centralnervous system CCK is not known with certainty, but it has beenimplicated in the control of feeding (Della-Fera and Baile, Science206:471-473, 1979).

Currently available appetite suppressant drugs either act peripherally,by increasing energy expenditure (such as thyroxine), or in some othermanner (such as the biguanides), or act by exerting a central effect onappetite or satiety.

Centrally acting appetite suppressants either potentiate centralcatecholamine pathways and tend to be stimulants (for example,amphetamine), or influence serotonergic pathways (for example,fenfluramine). Other forms of drug therapy include bulking agents whichact by filling the stomach, thereby inducing a "feeling" of satiety.

CCK is known to be present in some cortical interneurones which alsocontain gamma-aminobutyric acid (GABA) (H. Demeulemeester et al, JNeuroscience 8, 988-1000, 1988). Agents that modify GABA action may haveutility as anxiolytic or hypnotic agents (S. C. Harvey, ThePharmacological Basis of Therapeutics (7th ed.) 1985, pp 339-371,MacMillan). Thus, agents which modify CCK action may have parallelanxiolytic or hypnotic activities. The role of CCK in anxiety isdisclosed in TIPS 11:271-273, 1990.

SUMMARY OF THE INVENTION

The invention relates to novel compounds of the formula ##STR1## and thepharmaceutically acceptable salts thereof wherein R¹, R², R⁹, A, Ar² andw are as defined hereinbelow.

In commonly assigned copending application Ser. Nos. 07/576,308,07/576,628, 07/576,315, 07/576,024, 07/576,297, filed on Aug. 31, 1990and now abandoned by Horwell, et al, the disclosures of which areincorporated herein by reference CCK antagonists are disclosed.

In the continuation-in-part applications of the above application alsocommonly owned and copending Ser. Nos. 07/726,656 now U.S. Pat. No.5,331,006, 07/726,655 abandoned in favor of 08/839,647, abandoned infavor of 08/041,647, 07/726,653 now U.S. Pat. No. 5,340,825, 07/726,652,now U.S. Pat. No. 5,364,419 and 07/726,651 now U.S. Pat. No. 5,244,405filed on even date herewith by Horwell, et al, the disclosures of whichare incorporated herein by reference, CCK antagonists are disclosed.

The invention also relates to a pharmaceutical composition containing aneffective amount of a compound according to formula I in combinationwith a pharmaceutically acceptable carrier in unit dosage form effectivefor appetite suppression.

The compounds are also useful as anxiolytics, antipsychotics, especiallyfor treating schizophrenic behavior, as agents in treating disorders ofthe extrapyramidal motor system, as agents for blocking the trophic andgrowth stimulating actions of CCK and gastrin, and as agents fortreating gastrointestinal motility.

Compounds of the invention are also useful as analgesics and potentiatethe effect of morphine. They can be used as an adjunct to morphine andother opioids in the treatment of severe pain such as cancer pain andreduce the dose of morphine in treatment of pain where morphine iscontraindicated.

An additional use for compounds such as the iodinated compound is thatthe suitable radiolabelled iodine-131 or iodine-127 isotope gives anagent suitable for treatment of gastrin dependent tumors such as thosefound in colonic cancers. I-125 radiolabelled compound can also be usedas a diagnostic agent by localization of gastrin and CCK-B receptors inboth peripheral and central tissue.

The invention further relates to a method of appetite suppression inmammals which comprises administering an amount effective to suppressappetite of the composition described above to a mammal in need of suchtreatment.

The invention also relates to a pharmaceutical composition for reducinggastric acid secretion containing an effective amount of a compound offormula I in combination with a pharmaceutically acceptable carrier inunit dosage form effective for reducing gastric acid secretion.

The invention also relates to a method for reducing gastric acidsecretion in mammals which comprises administering an amount effectivefor gastric acid secretion reduction of the composition described aboveto a mammal in need of such treatment.

The invention also relates to a pharmaceutical composition containing aneffective amount of a compound of formula I in combination with apharmaceutically acceptable carrier in unit dosage form effective forreducing anxiety.

The invention also relates to a method for reducing anxiety in mammalswhich comprises administering an amount effective for anxiety reductionof the composition described above to a mammal in need of suchtreatment.

The invention also relates to a pharmaceutical composition containing aneffective amount of a compound of formula I in combination with apharmaceutically acceptable carrier in unit dosage form effective fortreating gastrointestinal ulcers.

The invention further relates to a method for treating gastrointestinalulcers in mammals which comprises administering an amount effective forgastrointestinal ulcer treatment of the composition as described aboveto a mammal in need of such treatment.

The invention also relates to a pharmaceutical composition containing aneffective amount of a compound of formula I in combination with apharmaceutically acceptable carrier in unit dosage form effective fortreating psychosis, i.e., schizophrenia.

The invention further relates to a method for treating psychosis inmammals which comprises administering an amount effective for treatingpsychoses of a composition as described above to a mammal in need ofsuch treatment.

The invention also relates to pharmaceutical compositions effective forstimulating or blocking CCK or gastrin receptors, for altering theactivity of brain neurons, for schizophrenia, for treating disorders ofthe extrapyramidal motor system, for blocking the trophic and growthstimulating actions of CCK and gastrin, and for treatinggastrointestinal motility.

The invention also relates to a pharmaceutical composition forpreventing the withdrawal response produced by chronic treatment orabuse of drugs or alcohol.

The invention further relates to a method for treating the withdrawalresponse produced by withdrawal from chronic treatment or withdrawalfrom abuse of drugs or alcohol. Such drugs include benzodiazepines,especially diazepam, cocaine, alcohol, and nicotine. Withdrawal symptomsare treated by administration of an effective withdrawal treating amountof a compound of the instant invention.

The invention also relates to a pharmaceutical composition containing aneffective amount of a compound of formula I in combination with apharmaceutically acceptable carrier in unit dosage form effective fortreating and/or preventing panic.

The invention also relates to a method for treating and/or preventingpanic in mammals which comprises administering an amount effective forpanic treatment and/or prevention of the composition described above toa mammal in need of such treatment.

The invention further relates to the use of the compounds of formula Ito prepare pharmaceutical and diagnostic compositions for the treatmentand diagnosis of the conditions described above.

The invention further provides processes for the preparation ofcompounds of formula I.

The invention further provides novel intermediates useful in thepreparation of compounds of formula I and also provides processes forthe preparation of the intermediates.

DETAILED DESCRIPTION

The compounds of the present invention are derivatives of α-methyltryptophan differing from natural dipeptides in that the substituentgroup R² is not hydrogen.

The compounds of the present invention are represented by the formula##STR2## or a pharmaceutically acceptable salt thereof wherein: R¹ is acyclo- or polycycloalkyl hydrocarbon of from three to twelve carbonatoms with from zero to four substituents, each independently selectedfrom the group consisting of: a straight or branched alkyl of from oneto six carbon atoms, halogen, CN, OR*, SR*, CO₂ R*, CF₃, NR⁵ R⁶, or--(CH₂)_(n) OR⁵, wherein R* is hydrogen, straight or branched alkyl offrom one to six carbon atoms, R⁵ and R⁶ are each independently hydrogenor alkyl of from one to six carbon atoms; and n is an integer from zeroto six;

A is --(CH₂)_(n) CO--, --SO₂ --, --SO--, --NHCO--, ##STR3## --SCO--,--O--(CH₂)_(n) CO-- or --HC═CHCO-- wherein n is an integer from zero tosix;

R² is a straight or branched alkyl of from one to six carbon atoms,--HC═CH₂, --C.tbd.CH, --(CH₂)_(n) --CH═CH₂, --(CH₂)_(n) C.tbd.CH,--(CH₂)_(n) Ar, --(CH₂)_(n) OR*, --(CH₂)_(n) OAr, --(CH₂)_(n) CO₂ R*,--(CH₂)_(n) NR⁵ R⁶ wherein n, R, R⁵, and R⁶ are as defined above and Aris a mono or polycyclic unsubstituted or substituted carbo- orheterocyclic aromatic or hydroaromatic moiety;

R⁹ is H, or a straight or branched alkyl of from one to six carbonatoms, --(CH₂)_(n) CO₂ R*, (CH₂)_(n) OAr', (CH₂)_(n) Ar', (CH₂)_(n) NR⁵R⁶, wherein n, R* R⁵, and R⁶ are as defined above and Ar' independentlytaken from Ar and w is zero or 1;

Ar² is ##STR4## wherein x and y are each independently O, S, N, CH₂,--CHR¹², --NR¹² --, --NR¹² CO--, --C═N--, --C═C--, or --C(═O) or a bond;o, p, q, and r are each independently an integer of from 0 to 3,provided that when o, p, q, and r are all simultaneously zero, Ar²becomes ##STR5## R¹², R¹³, and R¹⁴ are each independently halogen,

R² as is defined above,

--(CH₂)_(g) --B-D wherein g is an integer of from 0 to 6

wherein B is a bond, ##STR6## wherein R⁷ and R⁸ are independentlyselected from hydrogen and R², or together form a ring (CH₂)_(m) whereinm is an integer of from 1 to 5 and n is as defined above;

D is

--COOR*,

--CH₂ OR*,

--CHR² OR*,

--CH₂ SR*,

--CHR² SR*,

--CONR⁵ R⁶,

--CN,

--NR⁵ R⁶,

--OH,

--H, and acid replacements such as tetrazole, ##STR7## wherein s is aninteger of from 0 to 2 wherein R*, R², R⁵, and R⁶ are as defined above.

Other preferred compounds of the instant invention are those wherein

R¹ is ##STR8## wherein W, X, Y, and Z are each independently hydrogen, astraight or branched alkyl of from one to six carbon atoms, CF₃, NR⁵ R⁶,--(CH₂)_(n) CO₂ R*, or CN, F, Cl, Br, OR*, SR*, wherein R* is hydrogenor a straight or branched alkyl of from one to six carbon atoms and R⁵and R⁶ are as defined above and n is an integer of from 1 to 3.

A is --NHCO--,

--OCO--,

--SO₂ --,

--S(═O)--,

--CH₂ CO--,

R² is --CH₃,

--CH₂ CO₂ CH₃,

--CH₂ C.tbd.CH,

R⁹ is hydrogen,

when w is 1, Ar² is unsubstituted or substituted by one to threesubstituents each independently selected in the manner indicated abovesuch as ##STR9## and when w is zero, Ar² is unsubstituted or substitutedin the manner indicated above such as ##STR10##

More preferred compounds of the instant invention are those wherein

R¹ is 2-adamantyl or 1-(S)-endobornyl,

A is ##STR11## R² is --CH₃, X and Y are --CH₂ -- when p, q, and r are 1;and

Ar² is unsubstituted, or may be substituted by one to three substituentseach independently selected from --CH₂ OH, --CH₂ OCOCH₂ CH₂ COOH, --CH₂OCOCH═CHCO₂ H, --CH₂ NHCOCH₂ CH₂ COOH, --CH₂ NHCOCH═CHCO₂ H,--NHCOCH═CHCO₂ H, --NHCOCH₂ CH₂ CO₂ H, hydroxy, phenyl, CO₂ Me, benzyl,CONHCH₂ CH₂ CO₂ Bz, --CO₂ Bz, CH₂ SCH₂ CO₂ H, --CONHCH₂ CO₂ H, --CONHCH₂CH₂ CO₂ H, or --CH₂ SCH₂ CO₂ H.

Small x and small y can be independently carbonyl.

The D and the L configurations are possible at the chiral centers andare included in the scope of the invention:

Preferred is when R² is --CH₃ [D] configuration.

Preferred compounds of the instant invention are:

[2-[(2,2-Diphenylethyl)amino]1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamicacid, tricyclo[3.3.1.1³,7 ]dec-2-yl ester,

[2-[(3,4-dihydro-2H-1-benzopyran-3-yl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamicacid, tricyclo[3.3.1.1³,7 ]dec-2-yl ester,

[2-[(1H-inden-1-ylmethyl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamicacid, tricyclo[3.3.1.1³,7 ]dec-2-yl ester,

[2-[[(2,3-dihydro-1-hydroxy-1H-inden-1-yl)methyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamicacid, tricyclo [3.3.1.1³,7 ]dec-2-yl ester,

[1-(1H-indol-3-ylmethyl)-1-methyl2-oxo-2-[(1,2,3,4-tetrahydro-2-naphthalenyl)amino]ethyl]carbamic acid,tricyclo[3.3.1.1³,7 ]dec-2-yl ester,

[2-[(1,2-diphenylethyl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl2-oxoethyl]carbamic acid, tricyclo[3.3.1.1³,7 ]dec-2-yl ester,

[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[(1-phenyl-1-cyclopentyl)methyl]amino]ethyl]carbamicacid, tricyclo[3.3.1.1³,7 ]dec-2-yl ester,

[2-(dipentylamino)-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamicacid, tricyclo[3.3.1.1³,7 ]dec-2-yl ester,

[2-(3-azabicyclo[3.2.2]non-3-yl)-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamicacid, tricyclo[3.3.1.1³,7 ]dec2-yl ester,

[1-(1H-indol-3-ylmethyl)-2-(octahydro-1H -indol-1-yl)-1-methyl2-oxoethyl]carbamic acid, tricyclo[3.3.1.1³,7 ]dec-2-yl ester,

[2-(decahydro2-isoquinolinyl)-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamicacid, tricyclo[3.3.1.1³,7 ]dec-2-yl ester,

[2-[bis(phenylmethyl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl2-oxoethyl]carbamic acid, tricyclo[3.3.1.1³,7 ]dec-2-yl ester,

[2-(3-azaspiro[5.5]undec-3-yl)-1-(1H-indol-3-ylmethyl)-1-methyl2-oxoethyl]carbamic acid, tricyclo[3.3.1.1³,7 ]dec2-yl ester,

[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-yl)ethyl]carbamic acid, tricyclo[3.3.1.1³,7 ]dec-2-yl ester,

[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)ethyl]carbamicacid, tricyclo[3.3.1.1³,7 ]dec-2-yl ester.

Most preferred compounds of the instant invention are:

1. Carbamic acid,[2-[(2,3-dihydro-2-hydroxy-1H-inden-1-yl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]-,1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl ester (bicyclo ring is 1S-endo(+-isomer), trp center is D, indene ring centers are unknown),

2. Carbamic acid,[2-[(2,3-dihydro-1-hydroxy-1H-inden-2-yl)amino]-1-1H-indol-3-ylmethyl)-2-methyl-2-oxoethyl]-,1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl ester,[1S*[1α,2β[S-(trans)],4β]]- (Bicyclo system is 1S-endo),

3. Carbamic acid, [2-[(2,3-dihydro-1-hydroxy-1H-inden-2-yl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]-,1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl ester,[1S-[1α,2β[S*(1S*,2S*)],4α]]-[Bicyclo system is 1S-endo, all othercenters are R],

4. Carbamic acid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)amino]ethyl]-,1,7,7-trimethylbicyclo[2.2.1]hept-2-yl ester (Bicyclo system 1S-endo;TRP center R; naphthyl center (-) or (+)), (Isomer II),

5. Carbamic acid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-2,3,4-tetrahydro-1-oxo2-naphthalenyl) amino]ethyl]-, 1,7,7-trimethylbicyclo[2.2.1.1]hept-2-ylester (Bicyclo system 1S-endo; TRP center R; naphthyl center (+) or(-)), (Isomer I),

6. Carbamic acid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1,2,3,4-tetrahydro-1-naphthalenyl)amino]ethyl]-,tricyclo[3.3.1.1³,7 ]-dec-2-yl ester, (±)-,

7. Carbamic acid,[1-1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1,2,3,4-tetrahydro-2-naphthalenyl)naphthalenyl)amino]ethyl]-,tricyclo[3.3.1.1³,7 ]-dec-2-yl ester, (±)-,

8. Carbamic acid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethyl]-,tricyclo[3.3.1.1³,7 ]-dec-2-yl ester, (R)-,

9.4-[4-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]-2-phenyl-1-piperazinyl]-4-oxobutanoicacid (Isomer II) (Bicyclo system is 1S-endo, phenyl center is S or R,other center is R),

10.4-[4-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept2-yl)oxy]carbonyl]amino]propyl]-2-phenyl-1-piperazinyl]-4-oxobutanoicacid (Isomer I) (Bicyclo system is 1S-endo, phenyl center is R or S,other center is R),

11. 1,7,7-trimethylbicyclo[2.2.1]hept-2-ylmethyl)-1-methyl-2-oxo-2-(3-phenyl-1-piperazinyl)ethyl]carbamate(Bicyclo system is 1S -endo, phenyl is RS, other is R),

12.[1S-[1α,2β(S*),4α]]-4-[[[1-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]-4-phenyl-4-piperidinyl]methyl]amino]-4-oxobutanoicacid (Bicyclo system is 1S-endo),

13. 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl [1S-[1α,2β(S*),4α]]-[2-(4-hydroxy-4-phenyl-1-piperidinyl)-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate (Bicyclo system is1S-endo, TRP is R),

14.[1S-(1α,2β,4α)]-N-[N-[α-methyl-N-[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]-D-tryptophyl]-L-propyl]-β-alanine(Bicyclo system is 1S -endo),

15.Phenylmethyl[1S-(1α,2β,4α)]-1-[α-methyl-N-[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]-D-tryptophyl]-L-proline (Bicyclo system is 1S-endo),

16.[1S-[1α,2β(S*,R*),4α]]-[1-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]-3-pyrrolidinyl]methyl butanedioate,

17. Mono 1-[3-[(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[22.1]hept-2-yl)oxy]carbonyl]amino]propyl]-3-pyrrilidinyl-butanedioate(Bicyclo system is 1S-endo, pyrrolidine center is RS, other center isR),

18. 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl[2-(3-hydroxy-1-pyrrolidinyl)-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate(ring is 1S-endo, hydroxy center is RS, other center is R),

19. Phenylmethyl(1S-endo)N-[1-[α-methyl-N-[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]-D-tryptophyl]-L-prolyl]-β-alanine,

20.Methyl-N-[α-methyl-N-[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]-D-tryptophyl]-L-proline(mixture of 1S-exo and 1S-endo isomers),

21.N-[α-methyl-[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]-D-tryptophyl]-L-proline(mixture of 1S-exo and 1S-endo isomers),

22. Tricyclo[3.3.1.1³,7]dec-2-yl(±)-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1,2,3,4-tetrahydro-2-naphthalenyl)amino]ethyl]carbamate,

23. Tricyclo[3.3.1.1³,7]dec-2-yl(±)-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo2-[(1,2,3,4-tetrahydro-1-naphthalenyl)amino]ethyl]carbamate,

24.2,2,2-trifluoro-1-phenylethyl[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethylcarbamate (Isomer II) (tryptophancenter L or D hydroxy center S trifluoromethyl center R),

25.(R)-N-[1-[(methylphenylamino)carbonyl]-3-phenylpropyl]-1H-Indole-4-acetamide,

26.2-[[[(3-methylphenyl)amino]carbonyl]amino]-N-[2-(phenylmethyl)phenyl]acetamide,

27.[1S-[1α,2β(S*),4α]]-1,7,7-trimethylbicyclo[2.2.1]-hept-2-yl-[2-(3,4-dihydro-2(1H)-isoquinolinyl)-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate(Bicyclo system is 1S -endo),

28. Tricyclo[3.3.1.1³,7 ]dec-2-yl(±)-[2-[(2,3-dihydro-1H-inden2-yl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,

29. Tricyclo[3.3.1.1³,7]dec-2-yl(±)-[2-[(2,3-dihydro-1H-inden-1-yl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,

30. Tricyclo[3.3.1.1³,7 ]dec-2-yl-(R)-[1-(1H-indol-3-ylmethyl)-1-methyl2-oxo2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethyl]carbamate,

31.4-[[1,2,3,4-Tetrahydro-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-naphthalenyl]amino]-4-oxobutanoate,

32. Tricyclo[3.3.1.1³,7]dec-2-yl-[2-[(1-azido-1,2,3,4-tetrahydro-2-naphthalenyl)amino]-1(1H-indol-3-ylmethyl)-1-methyl 2-oxoethyl]carbamate,

33. Methyl3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-3-oxopropanoate,

34. Methyl3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-3-oxopropanoate,

35. Methyl 1-[[1,2,3,4-tetrahydro-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo [3.3.1.1³,7 ]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-naphthalenyl]amino]-4-oxo-2-butanoate, and

36. Tricyclo [3.3.1.1³.7 ]dec2-yl ester (R)[1-(1H-indol-3-ylmethyl)-2-[(4-methoxyphenyl)amino]-1-methyl-2-oxoethyl]carbamate.

Table I below illustrates representative compounds of the invention.Stereochemistry is not shown in the Table I in all instances. Thenumbers in the first column refer to the numbered compounds on theprevious pages.

                                      TABLE I                                     __________________________________________________________________________     ##STR12##                                                                    Compound Number                                                                         R.sup.1     A    R.sup.2                                                                           R.sup.9                                                                          w Ar.sup.2                                  __________________________________________________________________________               ##STR13##  OCO  Me  Null                                                                             0                                                                                ##STR14##                                2                                                                                        ##STR15##  OCO  Me (R)                                                                            H  1                                                                                ##STR16##                                3                                                                                        ##STR17##  OCO  Me (R)                                                                            H  1                                                                                ##STR18##                                4                                                                                        ##STR19##  OCO  Me (R)                                                                            H  1                                                                                ##STR20##                                5                                                                                        ##STR21##  OCO  Me (R)                                                                            H  1                                                                                ##STR22##                                6                                                                                        ##STR23##  OCO  Me (R)                                                                            H  1                                                                                ##STR24##                                7                                                                                        ##STR25##  OCO  Me (R, S)                                                                         H  1                                                                                ##STR26##                                8                                                                                        ##STR27##  OCO  Me (R, S)                                                                         H  1                                                                                ##STR28##                                27                                                                                       ##STR29##  O CO Me  H  1                                                                                ##STR30##                                28                                                                                       ##STR31##  OCO  Me  H  1                                                                                ##STR32##                                29                                                                                       ##STR33##  OCO  Me (S)                                                                            Null                                                                             0                                                                                ##STR34##                                36                                                                                       ##STR35##  OCO  Me  H  1                                                                                ##STR36##                                __________________________________________________________________________

In addition to the compounds of Table I the compounds of the presentinvention include compounds of formula I wherein the indole moiety is a2- or 3-indolyl.

The compounds include solvates and hydrates and pharmaceuticallyacceptable salts of the compounds of formula I.

The compounds of the present invention can have multiple chiral centersincluding those designated in the above formula I by an , depending ontheir structures. Centers of asymmetry may exist on substituents R¹, R⁹,and/or Ar². In particular the compounds of the present invention mayexist as diastereomers, mixtures of diastereomers, or as the mixed orthe individual optical enantiomers. The present invention contemplatesall such forms of the compounds. The mixtures of diastereomers aretypically obtained as a result of the reactions described more fullybelow. Individual diastereomers may be separated from mixtures of thediastereomers by conventional techniques such as column chromatographyor repetitive recrystallizations. Individual enantiomers may beseparated by convention method well known in the art such as conversionto a salt with an optically active compound, followed by separation bychromatography or recrystallization and reconversion to the nonsaltform.

The compounds of the present invention can be formed by couplingindividual substituted α-amino acids by methods well known in the art.(See, for example, standard synthetic methods discussed in themulti-volume treatise "The Peptides, Analysis, Synthesis, Biology," byGross and Meienhofer, Academic Press, New York.) The individualsubstituted alpha amino acid starting materials are generally known or,if not known, may be synthesized and, if desired, resolved by methodswithin the skill of the art. (Synthesis of racemic [DL]-α-methyltryptophan methyl ester--see Brana, M. F., et al, J. Heterocyclic Chem.17:829, 1980.)

A key intermediate in the preparation of compounds of formula I is acompound of formula ##STR37## wherein R is selected from R¹,9-fluorenylmethyl, Bz and other suitable N-blocking groups. These areuseful as intermediates in the preparation of compounds of formula I.The compounds wherein R is 1-adamantyl, 2-adamantyl, 4-protoadamantyl,exo-bornyl, endo-bornyl, exo-norbornyl, endo-norbornyl,2-methylcyclohexyl, 2-chlorocyclohexyl, or camphoryl are novel and arepreferred.

The disclosure of U.S. Pat. No. 4,757,151 is hereby incorporated byreference. It describes the 9-fluorenylmethyl blocking group.

Compounds of formula II are prepared by reacting

    ROH                                                        III

wherein R is as defined above, with phosgene or a phosgene substitute toproduce a corresponding compound of formula

    ROCOCl                                                     IV

and then reacting a compound of formula IV with α-methyltryptophan toproduce the desired compound of formula II above.

Alternatively, a compound of formula IV can be reacted with anα-methyltryptophan methyl ester to produce ##STR38## which can beconverted to a compound of formula II by known means such as hydrolysiswith aqueous lithium hydroxide.

Scheme I below illustrates procedures for preparing intermediates usefulin producing final products of formula I.

Key intermediate (2) is prepared from the alcohol form of a radicalselected from 1-adamantyl, 2-adamantyl, 4-protoadamantyl,9-fluorenylmethyl, exo-bornyl, endo-bornyl, exo-norbornyl,endo-norbornyl, 2-methylcyclohexyl, 2-chlorocyclohexyl, and camphoryl.The alcohol is dissolved in a solvent such as methylene chloride. It isthen converted to the corresponding chloroformate by reaction withbis(trichloromethyl) carbonate in pyridine at about 0° C. The product isformed by condensation with an amine such as α-methyl-D-tryptophanmethyl ester. The reaction is carried out in a solvent such as THF toproduce, for example, N-[(2-adamantyloxy)carbonyl]-α-methyl-D-tryptophanmethyl ester. This is then treated with lithium hydroxide and stirred atroom temperature overnight to produce the corresponding carboxylic acid.This novel key intermediate (2) is useful in the production of compoundsof formula I as described hereinafter in Schemes II and III.

Schemes IV through VIII correspond to Examples 7 through 17 andillustrate methods of preparing final products of formula I of theinstant invention. ##STR39##

Whenever R in intermediate of formula II is other than R¹, it may beremoved at an appropriate point in the synthesis by methods known in theart for each respective group and the desired R¹ substituted therefore.

BIOLOGICAL ACTIVITY

The biological activity of compounds of the present invention wasevaluated employing an initial screening test which rapidly andaccurately measured the binding of the tested compound to known CCKreceptor sites. Specific CCK receptors have been shown to exist in thecentral nervous system. (See Hays et al, Neuropeptides 1:53-62, 1980;and Satuer et al, Science 208:1155-1156, 1980.

In this screening test, the cerebral cortices taken from male CFLP miceweighing between 30-40 g were dissected on ice, weighed, and homogenizedin 10 volumes of 50 mM Tris-HCl buffer (pH 7.4 at 0°-4° C.). Theresulting suspension was centrifuged, the supernate was discarded, andthe pellet was washed by resuspension in Tris-HCl buffer followed byrecentrifugation. The final pellet was resuspended in 20 volumes of 10nM Hepes buffer (pH 7.2 at 23° C.) containing 130 mM NaCl, 4.7 nM KCl, 5nM MgCl₂, 1 nM EDTA, 5 mg/mL bovine albumin, and bacitracin (0.25mg/ml).

In saturation studies, cerebral cortical membranes were incubated at 23°C. for 120 minutes in a final volume of 500 μliter of Hepes incubationbuffer (pH 7.2) together with 0.2-20 nM tritiated-pentagastrin (AmershamInternational, England).

In the displacement experiments, membranes were incubated with a singleconcentration (2 nM) of ligand, together with increasing concentrations(10⁻¹¹ to 10⁻¹⁴ M) of competitive test compound. In each case, thenonspecific binding was defined as that persisting in the presence ofthe unlabeled octapeptide CCK₂₆₋₃₃ (10⁻⁶ M).

Following incubation, radioactivity bound to membranes was separatedfrom that free in solution by rapid filtration through Whatman GF/Bfilters and washed three times with 4 mL of ice cold Tris-HCl buffer.Filters from samples incubated with tritiated-pentagastrin were placedin polyethylene vials with 4 mL of scintillation cocktail, and theradioactivity was estimated by liquid scintillation spectrometry(efficiency 47-52%).

The specific binding to CCK receptor sites was defined as the totalbound tritiated-pentagastrin minus the amount of tritiated-pentagastrinbound in the presence of 10⁻⁶ octapeptide, CCK₂₆₋₃₃.

Saturation curves for specific tritiated-pentagastrin binding to mousecortical membranes were analyzed by the methods of Scatchard (Ann. NewYork Acad. Sci. 51:660-672, 1949, and Hill (J. Physiol. 40:IV-VIII,1910, to provide estimates for the maximum number of binding sites(B_(max)) and the equilibrium dissociation constant (K_(a)).

In displacement experiments, inhibition curves were analyzed by eitherlogit-log plots or the iterative curve fitting computer program ALLFIT(DeLean, Munson and Redbard, 1978) to provide estimates of the IC₅₀ andnH (apparent Hill coefficient) values). (IC₅₀ values were defined as theconcentration of test compound required to produce 50% inhibition ofspecific binding.)

The inhibition constant (K_(i)) of the test compound was then calculatedaccording to the Cheng-Prusoff equation: ##EQU1## where [L] is theconcentration of radiolabel and K_(a) is the equilibrium dissociationconstant.

The K_(i) values for several representative compounds of the presentinvention are present in Table II below.

                  TABLE II                                                        ______________________________________                                        Binding Data                                                                                   K.sub.i (nM)                                                                           K.sub.i (nM)                                        Compound Number  CCK B    CCK A                                               ______________________________________                                        1                280      N.T.                                                2                111      5300                                                3                30       3870                                                4                94       7620                                                5                59       N.T.                                                6                45       5220                                                7                330      N.T.                                                8                450      N.T.                                                36               33       N.T.                                                ______________________________________                                         N.T. = Not tested                                                             Compound numbers are from the list of compounds starting on page 17.     

Compounds of the present invention are expected to be useful as appetitesuppressants as based on the tests described hereinbelow.

In the Palatable Diet Feeding assay, adult male Hooded Lister ratsweighing between 200-400 g are housed individually and trained to eat apalatable diet. This diet consists of Nestles sweetened condensed milk,powdered rat food and rat water which when blended together set to afirm consistency. Each rat is presented with 20-30 g of the palatablediet for 30 minutes per day during the light phase of the light-darkcycle over a training period of five days. The intake of palatable dietis measured by weighing the food container before and after the30-minute access period (limits of accuracy 0.1 g). Care is taken tocollect and correct for any spillage of the diet. Rats have free accessto pellet food and water except during the 30-minute test period.

After the training period, dose-response curves are constructed for CCK8for several representative compounds of the present invention (n=8-10rats per dose level). MPE₅₀ values (±95% confidence limits) are obtainedfor the anorectic effects of these compounds.

In therapeutic use as appetite suppression agents, the compounds of theinstant invention are administered to the patient at dosage levels offrom about 200 to about 2800 mg per day.

Male Hooded Lister rats (175-250 g) are housed individually and fastedovernight (free access to water). They are anesthetized with urethane(1.5 g/kg IP) and the trachea cannulated to aid spontaneous respiration.The stomach is perfused continuously using a modification of theoriginal method of Ghosh & Schild in "Continuous recording of acidsecretion in the rat", Brit. J. Pharmac. 13:54-61, 1956 as described byParsons in "Quantitative studies of drug-induced gastric acidsecretion". (Ph.D. Thesis, University of London, 1969). The cavity ofthe stomach is perfused at a rate of 3 mL/min with 5.4% w/v glucosesolution through both the esophageal and body cannula. The fluid ispropelled by a roller pump (Gilson, Minipuls 2), through heating coilsto bring its temperature to 37°±1° C. The perfusion fluid is collectedby the fundic collecting funnel and passed to a pH electrode connectedto a Jenway pH meter (PHM6). An output is taken from the pH meter to aRikadenki chart recorder for the on-line recording of the pH of thegastric perfusate.

Pentagastrin is stored as a frozen aliquot and diluted to the requiredconcentrations with sterile 0.9% w/v NaCl. Novel compounds are dissolvedin sterile 0.9% w/v NaCl on the day of the experiment. Drugs areadministered IV through a cannulated jugular vein as a bolus in a dosevolume of 1 ml/kg washed in with 0.15 ml 0.9% w/v NaCl. Basal pH isallowed to stabilize before administration of compounds is begun.Typically 30 minutes elapses between surgery and the first compoundadministration.

With test compounds, the antagonism is expected to be reversible withfull recovery of the response to pentagastrin.

The compounds of the instant invention are also expected to be useful asantiulcer agents as discussed hereinbelow.

Aspirin-induced gastric damage is assessed in groups of 10 rats each.

All animals are fasted for 24 hours before and throughout theexperiment. Drug or vehicle are given 10 minutes before an oral dose of1 ml of a 45-mg/mL suspension of aspirin in 0.5% carboxymethylcellulose(CMC).

The animals are sacrificed 5 hours after aspirin administration and thestomachs removed and opened for examination.

Gastric damage was scored as follows:

    ______________________________________                                        Score                                                                         ______________________________________                                        1                 Small hemorrhage                                            2                 Large hemorrhage                                            3                 Small ulcer                                                 4                 Large ulcer                                                 5                 Perforated ulcer                                            ______________________________________                                    

The specific dosages employed, however, may be varied depending upon thepatient, the severity of the condition being treated, and the activityof the compound employed. Determination of optimum dosages is within theskill of the art.

The compounds of the instant invention are also expected to be useful asanxiolytic agents as described and discussed below.

Anxiolytic activity is assessed in the light/dark exploration test inthe mouse (B. J. Jones, et al, Brit. J. Pharmac. 93:985-993, 1988).

The pretreatment time is 40 minutes. The compound is given p.o. in 0.1,1, and 10 mg/kg doses.

The apparatus is an open-topped box, 45 cm long, 27 cm wide, and 27 cmhigh, divided into a small (2/5) area and a large (3/5) area by apartition that extended 20 cm above the walls. There is a 7.5×7.5 cmopening in the partition at floor level. The small compartment ispainted black and the large compartment white. The floor of eachcompartment is marked into 9 cm squares. The white compartment isilluminated by a 100-watt tungsten bulb 17 cm above the box and theblack compartment by a similarly placed 60-watt red bulb. The laboratoryis illuminated with red light.

All tests are performed between 13 hundred hours, 0 minutes and 18hundred hours, 0 minutes. Each mouse is tested by placing it in thecenter of the white area and allowing it to explore the novelenvironment for 5 minutes. Its behavior is recorded on videotape and thebehavioral analysis was performed subsequently from the recording. Fiveparameters are measured: the latency to entry into the dark compartment,the time spent in each area, the number of transitions betweencompartments, the number of lines crossed in each compartment, and thenumber of rears in each compartment.

In this test an increase in the time spent in the light area is asensitive measure of, that is directly related to, the anxiolyticeffects of several standard anxiolytic drugs. Drugs are dissolved inwater or saline and administered either subcutaneously,intraperitoneally, or by mouth (PO) via a stomach needle.

The compounds of the instant invention are useful as antipsychoticagents. Compounds are tested for their ability to reduce the effects ofintra-accumbens amphetamine in the rat as described hereinafter.

Male Sprague Dawley (CD) Bradford strain rats are used. The rats arehoused in groups of five at a temperature of 21°±2° C. on a 12 hourlight-dark cycle of lights-on between 07 hours 00 minutes and 20 hours00 minutes. Rats are fed CRM diet (Labsure) and allowed water adlibitum.

Rats are anesthetized with chloral hydrate (400 mg/kg SC) and placed ina Kopf stereotaxic frame. Chronically indwelling guide cannulae(constructed of stainless steel tubing 0.65 mm diameter held bilaterallyin Parspex holders) are implanted using standard stereotaxic techniquesto terminate 3.5 mm above the center of the nucleus accumbens (Ant. 9.4,Vert. 0.0, Lat. 1.6) or 5.0 mm above the central nucleus of the amygdala(Ant. 5.8, Vert. -1.8, Lat. ±4.5) (atlas of De Groot, 1959). The guidesare kept patent during a 14-day recovery period using stainless steelstylers, 0.3 mm diameter, which extended 0.5 mm beyond the guide tips.

Rats are manually restrained and the stylers removed. Intracerebralinjection cannulae, 0.3 mm diameter, are inserted and drugs delivered ina volume of 0.5 μL over 5 seconds (a further 55 seconds was allowed fordeposition) from Hamilton syringes attached via polythene tubing to theinjection units. Animals are used on a single occasion only.

Behavioral experiments are conducted between 07 hours 30 minutes and 21hours 30 minutes in a quiet room maintained at 22°±2° C. Rats are takenfrom the holding room and allowed one hour to adapt to the newenvironment. Locomotor activity is assessed in individual screenedPerspex cages (25×15×15 cm (high) (banked in groups of 30) each fittedwith one photocell unit along the longer axis 3.5 cm from the side; thisposition has been found to minimize spurious activity counts due to, forexample, preening and head movements when the animal is stationary.Interruptions of the light beam are recorded every 5 minutes. At thistime animals are also observed for the presence of any nonspecificchange in locomotor activity, e.g., sedation, prostration, stereotypedmovements, that could interfere with the recording of locomotoractivity.

The abilities of compounds to inhibit the hyperactivity caused by theinjection of amphetamine into the nucleus accumbens of the rat ismeasured.

An increase in locomotor activity followed the bilateral injection ofamphetamine (20 μg) into the nucleus accumbens; peak hyperactivity (50to 60 counts 5 minutes⁻¹) occurs 20 to 40 minutes after injection.

Intraperitoneal injection of the rats with a compound (20 mg/kg or 30mg/kg) or (10 mg/kg) reduces the hyperactivity caused by theintra-accumbens injection of amphetamine. This test is known to bepredictive of antipsychotic activity (Costall, Domeney & Naylor & Tyers,Brit. J. Pharmac. 92:881-894).

The compounds of the instant invention are expected to prevent and treatthe withdrawal response produced when chronic treatment by a drug isstopped or when alcohol abuse is stopped. These compounds are thereforeuseful as therapeutic agents in the treatment of chronic drug or alcoholabuse.

The effect of the compounds of the instant invention is illustrated, forexample, in the mouse "light/dark box" test.

Five animals are given nicotine, typically in a range of 0.01 to 100mg/kg i.p. b.d. for 14 days. After a 24-hour withdrawal period, acompound is given typically at a range of 0.01 to 100 mg/kg i.p. b.d.The increased time spent in the light area is a sensitive measure of theeffect of the compound as an agent to treat withdrawal effects fromnicotine.

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing suppository preparations, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmolds and allowed to cool and solidify.

The powders and tablets preferably contain 5 to about 70% of the activecomponent. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth,methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax,cocoa butter, and the like.

A preferred pharmaceutically acceptable salt is the N-methyl glucaminesalt.

The term "preparation" is intended to include the formulation of theactive component with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier which is thus in association with it.Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosageforms suitable for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions.Sterile water or water-propylene glycol solutions of the activecompounds may be mentioned as an example of liquid preparations suitablefor parenteral administration. Liquid preparations can also beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolvingthe active component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

Preferably the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofthe preparation, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of any of thesepackaged forms.

Examples are illustrative of methods of preparing the final products.

EXAMPLES Example 1

Carbamic acid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethyl]-,tricyclo[3.3.1.1³,7 ]dec-2-yl ester. (R)- ##STR40##

To a stirred solution of α-methyl-N-[(tricyclo[3.3.1.1³,7]dec-1-yloxy)carbonyl]-R-tryptophan (150 mg, 0.3 mmol) in anhydrousEtOAc (7 mL) was added N,N-dicyclohexylcarbodiimide (86 mg, 0.41 mmol)and pentafluorophenol (77 mg, 0.41 mmol). The reaction mixture wasstirred at room temperature for 2 hours and then 1,2,3,4-tetrahydroisoquinoline (51 mg, 0.38 mmol) in EtOAc (2 mL) added. Afterstirring for 3 days, the reaction mixture was filtered and the filtrateconcentrated in vacuo. The residue was chromatographed over reversephase silica using 4:1 MeOH:H₂ O as eluant to give the desired amide asan amorphous solid (83 mg, 43%); m.p. 95°-100° C.; IR (film) 3300, 2908,2854, 1696, and 1625 cm⁻¹ ; NMR (CDCl₃) δ1.40-1.90 (17H, m), 2.85 (2H,t, J 6 Hz), 3.50 (2H, m), 3.95 (2 H, br s), 4.75 (1H, m), 4.85 (2H, brs), 5.15 (1H, br s), 6.97 (1H, s), 7.10 (6H, m), 7.34 (1H, d, J 8 Hz),7.56 (1, d, J 8 Hz), 8.15 (1H, s); Anal. (C₃₂ H₃₇ N₃ O₃.0.5CHCl₃), C, H,N.

Examples 2 and 3

Carbamic acid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)amino]ethyl]-,1,7,7-trimethylbicyclo[2.2.1.1]hept-2-yl ester: (Bicyclo system 1S-endo:TRP center R; naphthyl center (+) and (-))

1-S-endoBornyloxycarbonyl-α-methyl-R-tryptophan (247 mg, 0.62 mmol) andpentafluorophenol (114 mg, 0.62 mmol) as a solution in EtOAc (15 mL) wastreated with dicyclohexylcarbodiimide (130 mg, 0.63 mmol) at 0° C. andleft 24 hours at 4° C. The mixture was then filtered and the filtrateadded to a stirred mixture of 2-amino-1-tetralone HCl salt (122 mg, 0.62mmol) and triethylamine (63 mg, 0.62 mmol) in EtOAc (10 mL) at 0° C. Thecombined mixture was left stirring at room temperature for 18 hoursbefore 4-dimethylamino pyridine (20 mg, 0.16 mmol) was added and themixture left a further 48 hours. The reaction mixture was then washedwith H₂ O (10 mL), 1M HCl (10 mL), and H₂ O (10 mL). The organic phasewas dried over MgSO₄ and concentrated in vacuo. The residue waschromatographed over silica gel twice, once using 1% MeOH in CH₂ Cl₂,then the two diastereoisomers were separated using 25% EtOAc in n-hexaneas eluants, to give Isomer I as a white solid (110 mg, 33%), and IsomerII as a noncrystalline solid (100 mg, 30%).

Example 2 ##STR41## Isomer I

m.p. 106°-112° C. (MeOH/H₂ O); [α]20D+33.2° (c=0.27, MeOH); IR (film)1699 and 1663 cm⁻¹ ; NMR (CDCl₃) δ0.82 (3H, s), 0.85 (3H, s), 0.90 (3H,s), 1.07 (1H, dd, J 13.5 and 3 Hz), 1.20-1.30 (2H, m), 1.64 (3H, s),1.65-1.90 (4H, m), 2.30-2.45 (1H, m), 2.75-2.79 (1H, m), 2.98 (1H, br d,J 16 Hz), 3.20-3.35 (1H, m), 3.43 (1H, d, J 14 Hz), 3.51 (1H, d, J 14Hz), 4.56 (1H, dt, J 13.5 and 5 Hz), 4.70-5.00 (1H, br), 4.90 (1H, br d,J 9 Hz), 5.37 (1H, br s), 7.05-7.40 (7H, m), 7.51 (1H, t, J 7 Hz), 7.61(1H, d, J 8 Hz), 7.98 (1H, d, J 8 Hz), 8.20 (1H, s); Anal. C₃₃ H₃₉ N₃O₄.0.75H₂ O; C, H, N.

Example 3 ##STR42## Isomer II

m.p. 106°-111° C.; [α]20D-12° (c=0.1, MeOH); IR (film) 1697 and 1662cm⁻¹ ; NMR (CDCl₃) δ0.85 (6H, s), 0.89 (3H, s), 1.03 (1H, dd, J 14 and 3Hz), 1.10-1.30 (2H, m), 1.61 (3H, s), 1.65-1.90 (4H, m), 2.30-2.40 (1H,m), 2.65 2.75 (1H, m), 2.96 (1H, br d, J 16 Hz), 3.20-3.30 (1H, m), 3.41(1H, d, J 15 Hz), 3.49 (1H, d, J 15 Hz), 4.57 (1H, dt, J 14 and 5 Hz),4.89 (1H, d, J 9 Hz), 5.37 (1H, br s), 7.00-7.40 (8H, m), 7.53 (1H, dt,J 7 and 1 Hz), 7.60 (1H, d, J 8 Hz), 7.96 (1H, 0, J 8 Hz), 8.18 (1H, brs); Anal. C₃₃ H₃₂ N₃ O₄ m 0.5 Hz; C, H, N.

Example 4 ##STR43##

A solution of the acid (Schemes II or III, No. 1) (199 mg, 0.50 mmol)and pentafluorophenol (92 mg, 0.5 mmol) in EtOAc (20 mL) was cooled to0° C. and a solution of N,N'-dicyclohexylcarbodiimide (108 mg, 0.525mmol) in EtOAc (5 mL) was added. This was stirred for 24 hours at 0° C.,filtered, and trans-2(R)amino 1-(R)hydroxy indane (75 mg, 0.5 mmol)added. This mixture was stirred at room temperature for 24 hours andthen the solvent was removed in vacuo. The residue was chromatographedusing 2% MeOH in CH₂ Cl₂ as eluant to give the product as a white solid(191 mg, 72%), m.p. 100°-103° C. (MeOH/H₂ O); IR (film) 3368, 2954,1696, and 1651 cm⁻¹ ; NMR (CDCl₃) δ0.82 (3H, s), 0.86 (3H, s), 0.90 (3H,s), 0.97 (1H, dd, J 14 and 3 Hz), 1.05-1.35 (2H, m), 1.63 (3H, s),1.65-1.90 (3H, m), 2.30-2.40 (1H, m), 2.60 (1H, dd, J 15 and 8.5 Hz),3.15 (1H, dd, J 15 and 8.5 Hz), 3.30 (1H, d, J 15 Hz), 3.53 (1H, d, J 15Hz), 4.15-4.25 (1H, m), 4.70-4.80 (1H, br s), 4.89 (1H, d, J 10 Hz),4.98 (1H, d, J 6.5 Hz), 5.16 (1H, brs), 6.75-6.85 (1H, brs), 7.07 (1H,d, J 2 Hz), 7.10-7.40 (7H, m), 7.62 (1H, d, J 8 Hz), 8.17 (1H, s); MS(FAB) m/e 3321.1 (100), 530 (83). Anal. C₃₂ H₃₉ N₃ O₄.0.25H₂ O; C, H, N.

Example 5 ##STR44##

Method exactly as for Example 4 (Scheme III No. 2), except using trans2(S) amino 1(S) hydroxy indane: yield 157 mg, 85%); m.p. 97°-103° C.(MeOH/H₂ O); IR (film) 3369, 2954, 1696, and 1659 cm⁻¹ ; NMR (CDCl₃)δ0.76 (3H, s), 0.82 (3H, s), 0.88 (3H, s), 0.94-1.00 (1H, m), 1.10-1.30(2H, m), 1.55 (3H, s), 1.60-1.80 (3H, m), 2.20-2.37 (1H, m), 2.60 (1H,brs), 2.77 (1H, dd, J 15.5 and 7 Hz), 3.12 (1H, dd, J 15.5 and 7 Hz),3.38 (1H, d, J 15 Hz), 3.51 (1H, d, J 15 Hz), 4.60-4.70 (1H, m), 4.71(0.5H, brs), 4.81 (0.5H, brs), 5.03 (1H, g, J 5 Hz), 5.08 (1H, s), 6.48(1H, d, J 8 Hz), 7.00-7.40 (8H, m), 7.62 (1H, d, J 8 Hz), 8.1 (1H, brs);Anal. C₃₂ H₃₉ N₃ O₄.0.25H₂ O; C, H, N.

Example 6 ##STR45##

Method exactly as for Example 4 (Scheme III No. 2) except using1-amino-2-hydroxyindane, yield 183 mg, 69%; m.p. 99°-106° C. (MeOH/H₂O); IR (film) 3339, 1699, and 1657 cm⁻¹ ; NMR (CDCl₃) δ0.81 (3H, 2xs,separation 1 Hz), 0.85 (3H, s), 0.89 (3H, 2xs, separation 2 Hz),0.90-1.00 (1H, m), 1.10-7.35 (2H, m), 1.60-1.85 (6H, m), 2.30-2.40 (1H,m), 2.85-2.95 (1H, m), 3.20-3.60 (3H, m), 4.20-4.30 (1H, m), 4.38 (0.5H,s), 4.50 (0.5H, s), 4.85-4.93 (1H, m), 5.07 (1H, q, J 7 Hz), 5.18 (0.5H,s), 5.28 (0.5H, s), 6.65 (1H, d, J 5.5 Hz), 6.80 (0.5H, d, J 7.5 Hz),6.85 (0.5H, d, J 7.5 Hz), 7.05-7.25 (6H, m), 7.37 (1H, d, J 8 Hz), 7.62(1H, d, J 8 Hz), 8.24 (1H, brs); Anal. C₃₂ H₃₉ N₃ O₄.0.5H₂ O; C, H, N.

Example 7 ##STR46##

Method exactly as for Example 4, except using 2Adoc-α-Me-RS-TrpOH (7)and 1-aminotetralin; yield 228 mg, 87%; m.p. 108°-116° C. (MeOH/H₂ O);IR (film) 3400-3200, 2907, 2855, 1704, 1652, and 1493 cm⁻¹ ; NMR (CDCl₃)δ1.45-1.55 (2H, m), 1.59 (3H, s), 1.70-2.05 (16H, m), 2.70-2.80 (2H, m),3.36 (0.5H, d, J 14.5 Hz), 3.37 (0.5H, d, J 14.5 Hz), 3.54 (0.5H, d, J14.5 Hz), 3.57 (0.5H, d, J 14.5 Hz), 5.05-5.15 (1H, m), 5.16 (0.5H, s),5.19 (0.5H, s), 6.34 (0.5H, d, J 6 Hz), 6.38 (0.5H, d, J 6 Hz),7.00-7.25 (7H, m), 7.3 (1H, d, J 8 Hz), 7.63 (1H, d, J 8 Hz), 8.17 (1H,s); MS (FAB) m/e 526.3 (100, 396.1 (33), 33.1 (31); Anal. C₃₃ H₃₉ N₃O₃.0.25H₂ O; C, H, N.

Example 8 ##STR47##

Method exactly as for Example 4, except using 2-Adoc-α-Me-RS-TrpOH (7)and 2-aminotetralin; yield 210 mg, 795, m.p. 97°-101° C. (MeOH/H₂ O); IR(film) 3400-3200, 2911, 2855, 1700, 1651, and 1495 cm⁻¹ ; NMR g(CDCl₃)δ1.50-2.00 (16H, m), 1.57 (1.5H, s), 1.58 (1.5H, s), 2.42 (0.5H, d, J7.5 Hz), 2.48 (0.5H, d, J 7.5 Hz), 2.70-3.05 (3H, m), 3.27 (0.5H, d, J14.5 Hz), 3.29 (0.5H, d, J 14.5 Hz), 3.51 (0.5H, d, J 14.5 Hz), 3.54(0.5H, d, J 14.5 Hz), 4.15-4.25 (1H, m), 4.80 (1H, d), 5.16 (0.5H, s),5.21 (0.5H, s), 6.10-6.20 (1H, brs), 6.99-7.21 (7H, m), 7.36 (1H, d, J 8Hz), 7.61 (1H, d, J 8 Hz), 8.12 (1H, s), MS (FAB) m/e 526.3 (100), 396.2(25), 330.2 (33); Anal. C₃₃ H₃₉ N₃ O₃.0.75H); C, H, N.

Example 9

Butanoic acid,4-oxo-4-[[1,2,3,4-tetrahydro-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]-dec-2-yloxy)carbonyl]amino]propyl]amino]-1-naphthalenyl]amino]-##STR48##

[1 alpha, 2 beta (R)]

Step 1. Carbamic acid,[2-[(1-azido-1,2,3,4-tetrahydro-2-naphthalenyl)amino]1-(1H-indol-3-yl-methyl)-1-methyl-2-oxoethyl]1-tricyclo[3.3.1.1³,7]dec-2-yl ester (See Scheme V) ##STR49##

A solution of 2-adamantyloxycarbonyl-α-methyl-R-tryptophan (3.00 g, 7.57mmol) and pentafluorophenol (1.39 g, 7.57 mmol) in EtOAc (80 mL) wascooled to 0° C. and treated with N,N'-dicyclohexylcarbodiimide (1.56 g,7.57 mmol). This reaction mixture was stirred for 30 minutes at 0° C.,filtered, and the filtrate treated with(±)trans-2-amino-1-azido-1,2,3,4-tetrahydronaphthalene (1.56 g, 8.32mmol) and allowed to warm to room temperature. After 48 hours thereaction mixture was washed with 1M citric acid solution (2×2 mL),saturated NaHCO₃ solution (2×20 mL), and H₂ O (2'20 mL). The organicphase was dried over MgSO₄ and the solvent evaporated in vacuo. Theresidue was separated by reverse phase silica gel chromatography using4:1 MeOH:H₂ O as eluant to give the product 5 as a noncrystalline whitesolid (3.71 g, 86%), m.p. 105°-110° C. [α]_(D) ²⁰ =+39.4° (c=0.5, MeOH);IR (film) 3500-3200, 2909, 2855, 2097, 1702, 1657, and 1493 cm⁻¹ ; NMR(CDCl₃) δ1.40 (1H, s), 1.45 (2.5H, s), 1.55 (1.5H, s), 1.65-1.90 (13H,m), 2.00-2.20 (1H, m), 2.60-2.75 (1H, m), 2.81 (0.5H, b, J 5.4 Hz), 2.87(0.5H, 5, J 5.3 Hz), 3.17- 3.27 (1H, m), 3.49 (0.5H, d, J 14.8 Hz), 3.56(0.5H, d, J 14.7 Hz), 4.18 (0.5H, d, J 4.6 Hz), 4.25-4.35 (1.5H, m),4.60-4.70 (1H, m), 5.04 (1H, s), 6.40-6.45 (0.5H, m), 6.46-6.55 (0.5H,m), 6.94 (1H, s), 7.05-7.30 (6H, m), 7.36 (1H, d, J 7.8 Hz), 7.55-7.65(1H, m), 8.11 (1H, s); MS m/e (FAB) 567 (5), 173 924), 146 (28), 135(100) and 109 (39).

Step 2. (Scheme V, No. 6) ##STR50##

A solution of thiazide from Step 1 (Scheme V, No. 5) (1.20 g, 2.11 mmol)in absolute EtOH (150 mL) was treated with Lundar catalyst (0.6 g, 50%w/w) and put under an atmosphere of hydrogen at a pressure of 50 psi for12 hours at room temperature. This was then filtered over gypsum andevaporated in vacuo to give the amine as a syrup (1.14 g, 100%). Thiswas used immediately in Step 3.

Step 3.

A solution of the amine from Step 2 (Scheme V, No. 6) (0.2 g, 0.37 mmol)in EtOAc (15 mL) was treated with succinic anhydride (0.044 g, 0.44mmol) and stirred at reflux with N,N-dimethyl amino pyridine (0.061 g,0.50 mmol) for 18 hours. This mixture was then evaporated to dryness andthe residue chromatographed over reverse phase silica using 5:1; MeOH:H₂O as eluent to give the product (Example 1) as a white solid (0.157 g,66%), m.p. 137°-150° C.; [α]_(D) ²⁰ =+32° (c=0.5, MeOH); IR (film)3500-3200, 2910, 2856, 1712, 1651, and 1531 cm⁻¹ ; NMR (DMSO-d₆ +D₂₀δ1.23 (1.5H, s), 1.29 (1.5H, s), 1.35-1.55 (2H, m), 1.60-2.00 (14H, m),2.20-2.55 (4H, m), 2.70-2.85 (2 H, m), 3.10-3.60 (2H, m), 3.85-4.00 (1H,m), 4.60-4.70 (1H, m), 5.00-5.10 (1H, M), 6.60-6.70 (1H, m), 6.85-7.25(7H, m), 7.31 (1H, d, J 8 Hz), 7.46 (1H, d, J 8 Hz), 7.30-7.55 (1H, m),8.23 (1H, d, J 9 Hz);

Analysis for C₃₇ H₄₄ N₄ O₆ : Calcd: C, 67.92; H, 7.00; N, 8.56. Found:C, 67.96; H, 6.87; N, 8.65.

Example 10 ##STR51##

Method exactly as for Example 9 except using glutaric anhydride in Step3 instead of succinic anhydride, m.p. 130°-142° C.; [α]_(D) ²¹ =410.8°(c=0.5, MeOH); IR (film) 3500-3200, 2919, 2854, 1710, 1651, and 1527cm⁻¹ ; NMR (CDCl₃) δ1.25 (1.5H, s), 1.35 91.5H, s), 1.40-1.55 (2H, m),1.15-2.05 (16H, m), 2.10-2.25 (2H, m), 2.50-2.55 (4H, m), 2.75-2.85 (2H,m), 3.90-4.05 (1H, m), 4.55-4.70 (1H, m), 5.00-5.10 (1H, m), 6.55-6.70(1H, m), 6.85-7.15 (7H, m), 7.31 (1H, d, J 8 Hz), 7.45-7.55 (1.5H, m),7.60-7.65 (10.5H, m), 8.15-8.25 (1H, m).

Examples 11 AND 12 (Scheme VI, No. 7a and 7b)

Propanoic acid,3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-3-oxo-,methyl ester (Isomer I) and Propanoic acid,3-[[2-[[3-1H-indol-3-yl)-2-methyl-1-oxo 2-[[(tricyclo3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-3-oxo-,methyl ester (Isomer II) ##STR52##

A solution of the amine from Example 10, Step 2 (Scheme V, No. 6) (0.20g, 0.4 mmol) in EtOAc (15 mL) was treated with methylmalonylchloride(0.06 g, 0.44 mmol) followed by triethylamine (0.03 g, 0.37 mmol) andstirred for 30 minutes at room temperature. This was then evaporated invacuo and the residue separated by silica gel chromatography using 1:1n-hexane:EtOAc as eluent to give two diastereoisomers separated asisomer I (0.05 g and Isomer II (0.06 g) (total yield 46%).

Isomer I: (Example 11, Propanoic acid,3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-3-oxo-, methyl ester), m.p. 140°-145° C.; [α]_(D) ²⁴ =+38.4° (c=0.25, MeOH);IR (film) 3500-3200, 2907, 2857, 1760-1700 (br), 1651, and 1491 cm⁻¹ ;NMR (CDCl₃) δ1.50-2.15 (19H, m), 2.75-2.87 (1H, m), 2.90-3.05 (1H, m),3.35 (2H, s), 3.40 (2H, s), 3.74 (3H, s), 3.95-4.05 (1H, m), 4.82 (1H,s), 5.15 (1H, b, J 10 Hz), 5.34 (1H, s), 6.86 (1H, d, J 7.5 Hz),7.00-7.35 (9H, m), 7.65 (1H, d, J 8 Hz), 8.17 (1H, s); MS m/e (FAB) 641(10), 263 (10), 173 (39), and 135 (100).

Analysis for C₃₇ H₄₄ N₄ O₆ : Calcd: C, 69.35; H, 6.92; N, 8.74. Found:C, 69.22; H, 6.86; N, 8.72.

Example 12

Propanoic acid,3-[[2-[[3-1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-3-oxo-,methyl ester, Isomer II

M.p. 142°-183.5° C.; [α]_(D) ²⁴ =+26.8° (c=2.5 MeOH); IR (film)3500-3200, 2910, 2854, 1760-1600 (br), 1651 and 1536 cm⁻¹ ; MR (CDCl₃)δ1.45-2.05 (18H, m), 2.15-2.30 (1H, m), 2.80-2.90 (1H, m), 2.95-3.10(1H, m), 3.24 (1H, d, J 17 Hz); 3.31 (1H, d, J 17 Hz), 3.39 (1H, d, J 15Hz), 3.45 (1H, d, J 15 Hz), 3.73 (3H, s), 3.95-4.10 (1H, m), 4.81 (1H,s), 5.17 (1H, t, J 7 Hz, 5.23 (1H, s), 6.93 (1H, d, J 7 Hz), 6.97 (1H,d, J 2 Hz), 7.05-7.30 (6H, m), 7.34 (1H, d, J 8 Hz), 7.38 (1H, d, J 9Hz), 7.60 (1H, d, J 8 Hz), 8.15 (1H, s); MS m/e (FAB) 641 (8), 263 (10),173 (40), and 135 (100).

Analysis for C₃₇ H₄₄ N₄ O₆.0.25 H₂ O: Calcd: C, 68.87; H, 6.95; N, 8.68.Found: C, 68.98; H, 7.08; N, 8.33.

Example 13 (Scheme VI, No. 11)

2-Butanoic acid,1-[[1,2,3,4,-tetrahydro-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-naphthalenyl]amino]-4-oxo-,methyl ester ##STR53##

[1 alpha (E), 2 beta (R)]

A solution of the amine from Example 9, Step 2 (Scheme V, No. 6) (0.6 g,1.1 mmol) in EtOAc (25 mL) was treated with methylpentafluorophenylfumarate (0.5 g, 1.7 mmol) and the resultant mixture stirred hours atroom temperature. The solvent was then removed in vacuo and the residuechromatographed over silica gel using 3:1 EtOAc:hexane as eluent to givethe product as a white, noncrystalline solid and a mixture of twodiastereoisomers (0.35 g, 50%); m.p.=234°-236° C.; [α]_(D) ²⁰ =+10.4°(c=0.5, MeOH); IR (film) 3500-3200, 2912, 2854, 1715, 1646, and 1538cm⁻¹ ; NMR (CDCl₃) δ1.34 (1.5H, s), 1.45-2.20 (17.5H, m), 2.70-2.90 (2H,m), 3.16 (0.5H, d, J 14.5 Hz), 3.27 (0.5H, d, J 6.5 Hz), 3.32 (0.5H, d,J 7 Hz), 3.42 (0.5H, d, J 14.5 Hz ), 3.72 (1.5H, s), 3.74 (1.5H, s),3.90-4.10 (1H, m), 4.75-4.85 (1H, m), 5.10-5.30 (2H, m), 6.70-7.35 (12H,m), 7.53 (0.5H, d, J 8 Hz), 7.60 (0.5H, d, J 8 Hz), 8.31 (0.5H, s), 8.37(0.5H, s).

Analysis for C₃₈ H₄₄ N₄ O₆.0.25H₂ O: Calcd: C, 69.44; H, 6.82; N, 8.52.Found: C, 69.55; H, 6.71; N, 8.49.

Example 14 (Scheme VIII, No. 20)

Butanoic acid,4-oxo-4-[[1,2,3,4-tetrahydro-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-naphthalenyl]amino]-##STR54## Step 1, Phenylmethyl(±)-trans-(1,2,3,4-tetrahydro-2-iodo-1-naphthalenyl)carbamate (SchemeVII, No. 13) ##STR55##

A solution of 1,2-dihydronaphthalene (10.0 g, 76.8 mmol) and iodine(19.5 g, 76.8 mmol) in anhydrous ether (200 mL) was treated with silvercyanate (17.27 g, 115.2 mmol) at 10° C. This mixture was stirred for 30minutes, allowed to warm to room temperature, and left stirring afurther 18 hours, then put under reflux for 1.5 hours. This suspensionwas then filtered, the filtrate evaporated to dryness in vacuo. Benzylalcohol (100 mL) was then added and the reaction mixture stirred for 3hours at room temperature. Excess benzyl alcohol was distilled off invacuo and the residue crystallized and recrystallized from methanol togive the benzyl urethane (19.12 g, 61%) as a white solid; m.p. 141.2° C.(MeOH); IR (film) 3500-3200, 1697, and 1518 cm⁻¹ ; NMR (CDCl₃)δ2.05-2.25 (2H, m), 2.75-2.85 (1H, m), 2.90-3.05 (1H, m), 4.55-4.70 (1H,br s), 5.05-5.25 (4H, m), 7.05-7.35 (9H, m).

Analysis for C₁₈ H₁₈ INO₂ : Calcd: C, 53.9; H, 4.45; N, 3.44. Found: C,53.29; H, 4.42; N, 3.45.

Step 2. Phenylmethyl(±)-cis-(2-azido-1,2,3,4-tetrahydro-1-naphthalenyl)carbamate (SchemeVII, No. 14) ##STR56##

A solution of the benzyl urethane from Step 1 (Scheme VII, No. 13) (7.62g, 18.7 mmol) in DMF (100 mL) was treated with sodium azide (1.46 g,22.5 mmol) and the resulting mixture stirred 18 hours at roomtemperature. The solvent was then removed in vacuo and the residuesuspended between H₂ O and EtOAc. The organic phase was washed withsaturated NaHCO₃ solution (2×20 mL), brine (2×20 mL), and H₂ O (2×20 mL)and then dried over MgSO₄, filtered, and the solvent removed in vacuo.The residue was crystallized and recrystallized from MeOH to give theazide (2.94 g, 49%), m.p. 103.7° C. (MeOH); NMR (CDCl₃) δ2.00-2.25 (2H,m), 2.70-2.85 (1H, m), 2.95-3.10 (1H, m), 4.05-4.20 (1H, br s),5.00-5.25 (4H, m), 7.05-7.40 (9H, m); IR (film) 3500-3200, 2101, 1697,and 1505 cm⁻¹.

Step 3. Phenylmethyl(±)-cis-(2-amino-1,2,3,4-tetrahydro-1-naphthalenyl)carbamate (SchemeVII, No. 15) ##STR57##

A solution of the azide from Step 2 (Scheme VII, No. 14) (2.00 g, 6.20mmol) in absolute EtOH (150 μL) was treated with Lindlar catalyst (1.0g, 50% w/w) and put under an atmosphere of hydrogen at a pressure of 50psi for 2 hours at 25° C. This mixture was then filtered over gypsum andthe filtrate evaporated to dryness in vacuo. The residue was separatedby column chromatography over silica gel using 10% MeOH in CH₂ Cl₂ aseluant to give the amine which was recrystallized from ether (1.3 g,67%), m.p. 102°-145° C. (Et₂ O); IR (film) 3500-3200, 1710, 1530, and1454 cm⁻¹ ; NMR (CDCl₃) δ1.70-1.95 (2H, m), 2.75-3.00 (2H, m), 3.15-3.25(1H, m), 4.80 (3H, s), 4.91 (1H, d, J 4 Hz), 5.10 (1H, d, J 12.5 Hz),5.16 (1H, d, J 12.5 Hz), 7.05-7.40 (9H, m).

Analysis for C₁₈ H₂₀ N₂ O₂ : Calcd: C, 72.94; H, 6.80; N, 9.45. Found:C, 72.84; H, 6.81; N, 9.44.

Step 4. Carbamic acid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[1,2,3,4-tetrahydro-1-[[phenylmethoxy)carbonyl]amino]2-naphthalenyl]amino]ethyl]tricyclo[3.3.1.1³,7]dec-2-yl ester (Scheme VII, No. 16) ##STR58##

A solution of 2-adamantyloxycarbonyl-α-methyl-1-tryptophan (5.94 g, 15.1mmol) and pentafluorophenol (2.78 g, 15.1 mmol) in EtOAc (150 mL) wastreated at 0° C. with N,N'-dicyclohexylcarbodiimide (3.11 g, 15.1 mmol).This mixture was stirred for 2 hours at 0° C., filtered, and the amineprepared in Step 3 (Scheme III, No. 15) (5.17 g, 16.6 mmol) was added tothe filtrate. This mixture was then stirred for 48 hours at roomtemperature before being washed with 1M citric acid solution (2×20 mL),saturated NaHCO₃ solution (2×20 mL), and H₂ O (2×20 mL). The organicphase was dried over MgSO₄, filtered, and the filtrate evaporated todryness in vacuo. The residue was separated by chromatography overreverse phase silica gel using MeOH:H₂ O (4:1) as eluant to give theproduct (7.21 g, 70%).

Step 5. Tricyclo[3.3.1.1³,7 ]dec-2yl[1R-[1α,2α(R*)]]and[1S-[1α,2α(S*)]]-[2-[(1-amino-1,2,3,4-tetrahydro-2-naphthalenyl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate(Scheme VII, No. 17) ##STR59##

A solution of the benzyl urethane from Step 4 (Scheme VII, No. 16) (1.0g, 1.5 mmol) in absolute EtOH (150 mL) was treated with 10% palladium oncarbon (0.2 g, 20% w/w) and put under an atmosphere of hydrogen at apressure of 50 psi at 25° C. for 4 hours. The mixture was then filteredover celite and the filtrate evaporated to dryness in vacuo to give theproduct (0.79 g, 100%), which is used immediately in the next step.

Step 6. [1R-[1α,2α(R*)] and[1S-[1α,2α(S*)]]-4-[[decahydro-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-naphthalenyl]amino]-4-oxobutanoicacid (Scheme VIII, No. 20) ##STR60##

A solution of the amine prepared in Step 5 (Scheme VII, No. 17) (0.4 g,0.73 mmol) in EtOAc (30 mL) was treated with succinic anhydride (0.09 g,0.9 mmol) and the resulting solution stirred 18 hours at roomtemperature. The mixture was then washed with 1M HCl solution (20 mL),saturated NaHCO₃ solution (2×20 mL), and H₂ O (2×20 mL). The organicphase was dried over MgSO₄, filtered, and the filtrate evaporated todryness in vacuo. The residue was separated over reverse phase silicagel using MeOH:H₂ O (3:1) as eluant to give the product as anoncrystalline white solid (0.27 g, 57%), m.p. 213°-238° C.; IR (film)3500-3200, 2911, 2852, 1696, 1661, and 1515 cm⁻¹ ; NMR (DMSO-d₆, D₂ O)δ1.27 (1.5H, s), 1.35 (1.5H, s), 1.36-1.50 (2H, m), 1.67-2.06 (14H, m),2.17-2.40 (4H, m), 2.60-2.95 (2H, m), 3.12 (0.5H, d, J 14.5 Hz),3.18-3.34 (1H, m), 3.39-3.55 (0.5H, m), 4.00-4.15 (1H, br s), 4.57- 4.67(1H, br s), 5.12 (0.5H, d, J 4.4 Hz), 5.15 (0.5H, d, J 4.4 Hz),6.85-6.98 (1H, m), 6.97-7.24 (6H, m), 7.30 (0.5H, d, J 8 Hz), 7.31(0.5H, d, J 8 Hz), 7.40-7.55 (1H, m).

Example 15 (Scheme VIII, No. 21)

Pentanoic acid,5-oxo-5-[[1,2,3,4-tetrahydro-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-naphthalenyl]amino]-[1S-[1.alpha.,2α(S*)]]and [1R[1α,2α(R*)]] ##STR61##

Method exactly as for Example 14 except using glutaric anhydride in Step6 instead of succinic anhydride (yield 0.29 g, 60%), m.p. 196°-206° C.;IR (film) 3500-3200, 2924, 2856, 1712, 1659, and 1515 cm⁻¹ ; NMR(DMSO-d₆, D₂ O) δ1.27 (1.5H, s), 1.31 (1.5H, s), 1.37-1.53 (2H, m),1.57-2.25 (20H, m), 2.60-2.95 (2H, m), 3.10 (0.5H, d, J 14.5 Hz), 3.28(0.5H, d, J 16.3 Hz), 3.37 (0.5H, d, J 16.3 Hz), 3.39-4.50 (0.5H, m),3.97-4.18 (1H, br s), 4.53-4.66 (1H, br s), 5.13 (0.5H, d, J 4 Hz),5.17-5.23 (0.5H, br s), 6.83-7.24 (7H, m), 7.31 (1H, d, J 7.3 Hz), 7.44(0.5H, d, J 8.5 Hz), 7.46 (0.5H, d, J 8 Hz).

Example 16 (Scheme VIII, No. 18)

Propanoic acid,3-oxo-3-[[1,2,3,4-tetrahydro-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-naphthalenyl]amino]-,methylester ##STR62##

A solution of the amine as prepared in Example 14, Step 5 (Scheme VII,No. 17) (0.8 g, 1.5 mmol) and methyl malonyl chloride (0.24 g, 1.77mmol) in EtOAc (60 mL) was treated with triethylamine (0.15 g, 1.48mmol) and the resulting mixture stirred 18 hours at room temperature.This mixture was then washed with 1M citric acid solution (3×20 mL),saturated NaHCO₃ solution (2×20 mL), and H₂ O (2×20 mL). The organicphase was dried over MgSO₄, filtered, and filtrate evaporated in vacuoto dryness. The residue was then purified by reverse phase silica gelchromatography using MeOH:H₂ O (3:1) as eluant to give the product, m.p.130.7°-154.9° C.

Example 17 (Scheme VIII, No. 22)

2-Butenoic acid,4-oxo-4-[[1,2,3,4-tetrahydro-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³.7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-naphthalenyl]amino]-, methylester ##STR63##

A solution of the amine as prepared in Example 14, Step 5 (Scheme VII,No. 17) (0.8 g, 1.5 mmol) in EtOAc (60 mL) was treated with methyl(pentafluorophenyl)fumarate (0.65 g, 2.22 mmol) and stirred for 12 hoursat room temperature. The mixture was evaporated to dryness in vacuo andthe residue separated by reverse phase silica gel chromatography usingMeOH:H₂ O (3:1) as eluant to give the product (0.52 g, 56%), m.p.142.6°-146.1° C.

Example 18

Tricyclo[3.3.1.1³.7 ]dec-2-yl ester (R)[1-(1H-indol-3-ylmethyl)-2-[(4-methoxyphenyl)amino]-1-methyl-2-oxoethyl]carbamate##STR64## Step 1

N,N¹ -dicyclohexylcarbodiimide (0.460 g, 2.24 mmol) was added to astirred solution of 2-Adoc-R-α-Me-Trp-OH (0.810 g, 2.04 mmol) and1-hydroxybenzotriazole monohydrate (0.380 g, 2.45 mmol) in EtOAc (80mL). The mixture was stirred for 1 hour at room temperature and the N,N¹-dicyclohexylurea filtered off. ₋₋₋₋ -anisidine (0.280 g, 2.24 mmol) wasadded followed by 4-dimethylaminopyridine (0.024 g, 0.20 mmol) and themixture stirred at room temperature for 72 hours. The EtOAc solution waswashed with 5% citric acid (2×25 mL), saturated NaHCO₃ solution (2×25mL) 5% citric acid (25 mL), and once with brine (25 mL). The EtOAc wasdried over MgSO₄, filtered and the solvent removed in vacuo. The residuewas purified by chromatography on silica using 67% n-hexane/33% EtOAc aseluant giving the product as a white solid (0.584 g, 57%); mp 111°-115°C.; [α]_(D) ²⁰ +39.8° (C=0.12, acetone); IR(film) 3327, 2914, 1701 and1671 cm⁻¹ ; δNMR (CDCl₃) 1.43-1.55 (2H, m), 1.64 (3H, s), 1.66-1.99(12H, m), 3.35 (1H, d, J 14.7 Hz), 3.57 (1H, d, J 14.6 Hz), 3.77 (3H,s), 4.87 (1H, s), 5.23 (1H, m), 6.82 (2H, d, J 9.0 Hz), 6.99 (1H, s),7.06-7.10 (1H, m), 7.15-7.20 (1H, m), 7.29-7.36 (3H, m), 7.60 (1H, d, J7.9 Hz), 8.18 (1H, b), 8.32 (1mH, s).

Analysis calculated for (C₃₀ H₃₅ N₃ O₄): C, H, N.

We claim:
 1. A method of blocking drug or alcohol withdrawal reaction ina mammal comprising administering an effective withdrawal reactionblocking amount of a compound of formula I ##STR65## or apharmaceutically acceptable salt thereof wherein: R¹ is a ##STR66##wherein W, X, Y, and Z are each independently hydrogen, a straight orbranched alkyl of from one to six carbon atoms, CF₃, NR⁵ R⁶, --(CH₂)_(n)CO₂ R═, or CN, F, Cl, Br, OR*, SR*, wherein R* is hydrogen or a straightor branched alkyl of from one to six carbon atoms and wherein R⁵ and R⁶are each independently hydrogen or alkyl of from one to six carbon atomsand n is an integer of from one to three;A is --(CH₂)_(n) CO--, --SO₂,--SO--, --NHCO--, ##STR67## --SCO--, --O--(CH₂)_(n) CO-- or --HC═CHCO--wherein n is an integer from zero to six; R² is a straight or branchedalkyl of from one to six carbon atoms, --HC═CH₂, --C.tbd.CH, --(CH₂)_(n)--CH═CH₂, --(CH₂)_(n) C.tbd.CH, --(CH₂)_(n) OR*, --(CH₂)_(n) CO₂ R*,--(CH₂)_(n) NR⁵ R⁶ wherein n, R*, R⁵, and R⁶ are as defined above; R⁹ isH, or a straight or branched alkyl of from one to six carbon atoms,--(CH₂)_(n) CO₂ R*, (CH₂)_(n) NR⁵ R⁶, wherein n, R*, R⁵, and R⁶ are asdefined above and w is 1; Ar² is ##STR68##
 2. A method of blocking drugor alcohol withdrawal reaction in a mammal comprising administering aneffective withdrawal reaction blocking amount of a compound of formula I##STR69## or a pharmaceutically acceptable salt thereof wherein: R¹ is##STR70## wherein W, X, Y, and Z are each independently hydrogen, astraight or branched alkyl of from one to six carbon atoms, F, Cl, Br,CN, OR*, SR*, CO₂ R*, CF₃, NR⁵ R⁶, or --(CH₂)_(n) OR⁵, wherein R* ishydrogen, straight or branched alkyl of from one to six carbon atoms, R⁵and R⁶ are each independently hydrogen or alkyl of from one to sixcarbon atoms; and n is an integer from one to three;A is --(CH₂)_(n)CO--, --SO₂ --, --SO₂ --, --NHCO--, ##STR71## --SCO--, --O--(CH₂)_(n)CO-- or --HC═CHCO-- wherein n is an integer from zero to six; R² is astraight or branched alkyl of from one to six carbon atoms, --HC═CH₂,--C.tbd.CH, --(CH₂)_(n) --CH═CH₂, --(CH₂)_(n) C.tbd.CH, --(CH₂)_(n) Ar,--(CH₂)_(n) OR* , --(CH₂)_(n) OAr, --(CH₂)_(n) CO₂ R*, --(CH₂)_(n) NR⁵R⁶ wherein n, R*, R⁵, and R⁶ are as defined above and Ar is a mono orpolycyclic unsubstituted or substituted carbo- or heterocyclic aromaticor hydroaromatic moiety; R⁹ is H, or a straight or branched alkyl offrom one to six carbon atoms, --(CH₂)_(n) CO₂ R*, (CH₂)_(n) OAr',(CH₂)_(n) AR', (CH₂)_(n) NR⁵ R⁶, wherein n, R*, R⁵, and R⁶ are asdefined above and Ar' is taken independently from Ar and w is zero or 1;Ar² is ##STR72## wherein m is an integer of from 1 to
 5. 3. A methodaccording to claim 2 wherein the compound administered is selected fromcarbamic acid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethyl]-,tricyclo[3.3.1.1³,7 ]-dec-2-yl ester, (R)-; or tricyclo[3.3.1.1³,7]dec-2-yl ester (R)[1-(1H-indol-3-ylmethyl)-2-[(4-methoxyphenyl)amino]-1-methyl-2-oxoethyl]carbamate.4. A method according to claim 1 wherein the compound administered isselected from carbamic acid,[2-[(2,3-dihydro-2-hydroxy-1H-indenl-yl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl],1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl ester (bicyclo ring is 1S-endo(+-isomer), trp center is D, indene ring centers are unknown);carbamicacid,[2-[(2,3-dihydro-1-hydroxy-1H-inden-2-yl)amino]-1-1H-indol-3-ylmethyl)-2-methyl-2-oxoethyl]-,1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl ester, [1S*[[1α,2β[S-(trans)],4β]]-(Bicyclo system is 1S-endo), and carbamic acid,[2-[(2,3-dihydro-1-hydroxy-1H-inden-2-yl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]-,1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl ester,[1S-[1α,2β[S*(1S*,2S*)],4α]]-[Bicyclo system is 1S-endo, all othercenters are R]; or carbamic acid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl-)amino]ethyl]-,1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl ester (Bicyclo system 1S-endo;TRP center R; naphthyl center (-) or (+)), (Isomer II) and carbamicacid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-2,3,4-tetrahydro-1-oxo-2-naphthalenyl-)amino]ethyl]-,1,7,7-trimethylbicyclo[2.2.1.1]hept-2-yl ester (Bicyclo system 1S-endo;TRP center R; naphthyl center (+) or (-)), (Isomer I); or carbamic acid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1,2,3,4-tetrahydro-1-naphthalenyl)amino]ethyl]-,tricyclo[3.3.1.1³,7 ]dec-2-yl ester, (±)- and carbamic acid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1,2,3,4-tetrahydro-2-naphthalenyl)amino]ethyl]-,tricyclo[3.3.1.1³,7 ]-dec-2-yl ester, (±)-; or4-[[1,2,3,4-tetrahydro-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-naphthalenyl]amino]-4-oxobutanoate;or tricyclo[3.3.1.1³,7]dec-2-yl-[2-[(1-azido-1,2,3,4-tetrahydro-2-naphthalenyl]amino]-1(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate;or methyl3-[[-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec2-yloxy)carbonyl]amino]propyl]amino]-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-3-oxopropanoate;or methyl3-[[-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-3-oxopropanoate;or methyl1-[[1,2,3,4-tetrahydro-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-naphthalenyl]amino]-4-oxo-2-butanoate.